DESCRIPTION: (Applicant's Abstract) Substance abuse is the major health problem in the United States. The cost to society in terms of death, disease, injury and emotional distress attributable to alcohol, nicotine, and other drugs is immeasurable. The goal of researchers interested in the neurobiological substrates of drug abuse is to understand the powerful motivating and addictive properties of drugs, and to develop better treatments for intoxication, craving, and relapse. In recent years, much progress has been made toward the first part of this goal. The neural pathways governing the reinforcing effects of drugs are well known, and very recently remarkable advances have been achieved in learning about effects of drugs on molecular mechanisms and gene expression. The objective of this proposal is to study in detail the basic behavioral functions of the nucleus accumbens, integrating behavioral, pharmacological and molecular approaches. The nucleus accumbens, located within the ventromedial striatum, is an important neural substrate for drug reinforcement. It is assumed, therefore, that since drugs appear to exert their rewarding properties in this region and its associated circuits, the accumbens may play a fundamental role in biological reinforcement and regulation of appetitive behaviors. Relatively little is known, however, about the specific neuromolecular mechanisms that underlie the functions of the accumbens. The aims of this project are to investigate the behavioral functions of the recently designated "core" and "shell" subregions of the nucleus accumbens. Specifically, we will 1) investigate the role of dopaminergic and glutamatergic receptor mechanisms and their associated intracellular mechanisms within the accumbens core in response-reinforcement learning, and 2) we will study transmitter mechanisms and circuitry involved in controlling feeding behavior located within the accumbens shell. Techniques to be utilized include local microinfusions of specific compounds that act of receptor and intracellular transduction mechanisms, in combination with behavioral analysis, and measurement of transcription factors and phosphorylating enzymes that may play a role in learning or motivated behavior. Further basic understanding of the systems and substrates upon which drugs act, which could potentially result from this research, could help to develop better addiction therapies.